OBJECTIVE: To explore the effects of Zishen Yutai Pills (ZYPs) on the quality of oocytes and embryos, as well as pregnancy outcomes in patients with diminished ovarian reserve (DOR) receiving in vitro fertilization-embryo transfer (IVF-ET). The possible mechanisms, involving the regulation of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), were also investigated. METHODS: A total of 120 patients with DOR who underwent their IVF-ET cycle were randomly allocated to 2 groups in a 1:1 ratio. The patients in the treatment group (60 cases) received ZYPs from the mid-luteal phase of the former menstrual cycle by using gonadotropin-releasing hormone (GnRH) antagonist protocol. The patients in the control group (60 cases) received the same protocol but without ZYPs. The primary outcomes were the number of oocytes retrieved and high-quality embryos. Secondary outcomes included other oocyte or embryo indices as well as pregnancy outcomes. Adverse events were assessed by comparison of the incidence of ectopic pregnancy, pregnancy complications, pregnancy loss, and preterm birth. Contents of BMP15 and GDF9 in the follicle fluids (FF) were also quantified with enzyme-linked immunosorbent assay. RESULTS: Compared with the control group, the numbers of oocytes retrieved and high-quality embryos were significantly increased in the ZYPs group (both P<0.05). After treatment with ZYPs, a significant regulation of serum sex hormones was observed, including progesterone and estradiol. Both hormones were up-regulated compared with the control group (P=0.014 and 0.008), respectively. No significant differences were observed with regard to pregnancy outcomes including implantation rates, biochemical pregnancy rates, clinical pregnancy rates, live birth rates, and pregnancy loss rates (all P>0.05). The administration of ZYPs did not increase the incidence of adverse events. The expressions of BMP15 and GDF9 in the ZYPs group were significantly up-regulated compared with the control group (both P<0.05). CONCLUSIONS ZYPs exhibited beneficial effects in DOR patients undergoing IVF-ET, resulting in increments of oocytes and embryos, and up-regulation of BMP15 and GDF9 expressions in the FF. However, the effects of ZYPs on pregnancy outcomes should be assessed in clinical trials with larger sample sizes (Trial reqistration No. ChiCTR2100048441).
Infant, Newborn ; Pregnancy ; Female ; Humans ; Fertilization in Vitro/methods* ; Ovarian Reserve ; Prospective Studies ; Premature Birth ; Embryo Transfer/methods* ; Ovulation Induction/methods* ; Gonadotropin-Releasing Hormone/therapeutic use*

Diminished ovarian reserve (DOR), generally defined as a decreased number or quality of oocytes, has a significant impact on quality of life and fertility in women. In recent years, the incidence of DOR has been increasing and the ages of patients are younger. The search for an effective DOR treatment has emerged as one of the preeminent research topics in reproductive health. An effective DOR therapy would improve ovarian function, fertility, and quality of life in patients. In this review we evaluated DOR treatment progress both in Western medicine and Chinese medicine, and elucidated the characteristics of each treatment.
Female ; Humans ; Medicine, Chinese Traditional ; Ovarian Reserve ; Quality of Life ; Oocytes ; Treatment Outcome ; Infertility, Female/therapy*

This study aims to investigate the efficacy and possible mechanism of Liuwei Dihuang Pills in the treatment of diminished ovarian reserve(DOR) by using proteomic techniques. Firstly, cyclophosphamide(60 mg·kg~(-1)) combined with busulfan(6 mg·kg~(-1)) was injected intraperitoneally to establish the mouse model of DOR. After drug injection, the mice were continuously observed and the success of modeling was evaluated by the disturbance of the estrous cycle. After successful modeling, the mice were administrated with the suspension of Liuwei Dihuang Pills by gavage for 28 days. At the end of the gavage, four female mice were selected and caged together with males at a ratio of 2∶1 for the determination of the pregnancy rate. Blood and ovary samples were collected from the remaining mice on the next day after the end of gavage. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were then employed to observe the morphological and ultrastructural changes in the ovaries. The serum levels of hormones and oxidation indicators were measured by enzyme-linked immunosorbent assay. Quantitative proteomics techniques were used to compare the ovarian protein expression before and after modeling and before and after the intervention with Liuwei Dihuang Pills. The results showed that Liuwei Dihuang Pills regulated the estrous cycle of DOR mice, elevated the serum levels of hormones and anti-oxidation indicators, promoted follicle development, protected the mitochondrial morphology of ovarian granulosa cells, and increased the litter size and survival of DOR mice. Furthermore, Liuwei Dihuang Pills negatively regulated the expression of 12 differentially expressed proteins associated with DOR, which were mainly involved in lipid catabolism, inflammatory response, immune regulation, and coenzyme biosynthesis. These differentially expressed proteins were significantly enriched in sphingolipid metabolism, arachidonic acid metabolism, ribosomes, ferroptosis, and cGMP-PKG signaling pathway. In summary, the occurrence of DOR and the treatment of DOR with Liuwei Dihuang Pills are associated with multiple biological pathways, mainly including oxidative stress response, inflammatory response, and immune regulation. "Mitochondria-oxidative stress-apoptosis" is the key to the treatment of DOR by Liuwei Dihuang Pills. YY1 and CYP4F3 may be the key upstream targets that trigger mitochondrial dysfunction and ROS accumulation, and the metabolism of arachidonic acid is the main signaling pathway of drug action.
Female ; Male ; Pregnancy ; Animals ; Mice ; Arachidonic Acid ; Ovarian Reserve ; Proteomics ; Ovary ; Lipid Metabolism

To summarize LIU Zhi-shun's clinical experience in treatment of infertility with decreasing ovarian reserve (DOR) with electroacupuncture. LIU Zhi-shun believes that the location of infertility with DOR is the uterus, mainly involving the kidney, thoroughfare and conception vessels. He advocates to select acupoints by combining "disease-symptom-position" with prescription, and selects acupoint prescription of Bushen Tiaochong Zhuyun included Guanyuan (CV 4), Zigong (EX-CA 1), Tianshu (ST 25), Sanyinjiao (SP 6), Ciliao (BL 32) and Zhongliao (BL 33) for electroacupuncture treatment. The key points of operation are accurate positioning and deep acupuncture, focusing on regulating mind and getting qi, adopting electroacupuncture treatment and low frequency stimulation and treating slowly for long-term disease.
Acupuncture Points ; Acupuncture Therapy ; Electroacupuncture ; Female ; Humans ; Infertility ; Ovarian Reserve

OBJECTIVE: To explore the therapeutic effect of Bushen Yiqi Huoxue Decoction BYHD) in patients with diminished ovarian reserve (DOR). METHODS: A total of 180 patients with DOR diagnosed from December 2013 to December 2014 were equally assigned into progynova and duphaston (E+D) group, Zuogui Pill group and BYHD group with 60 cases in each by computerized randomization. Patients received E+D, Zuogui Pill or BYHD for 12 months, respectively. Follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E₂), anti-Müllerian hormone (AMH), antral follicle count (AFC), ovarian volume, endometrial thickness, and the resistance indices (RIs) of ovarian arteries and uterine arteries were observed before and after treatment. RESULTS: Nine women (4 from the E+D group, 3 from the Zuogui Pill group, and 2 from the BYHD group) withdrew from the study. After 6 months, Zuogui Pill and BYHD significantly decreased FSH and LH and increased endometrial thickness and AMH (all P<0.01). BYHD also resulted in E₂ elevation (P<0.05), ovary enlargement (P<0.05), AFC increase (P<0.01), and RI of ovarian arteries decrease (P<0.05). After 12 months, further improvements were observed in the Zuogui Pill and BYHD groups (all P<0.01), but BYHD showed better outcomes, with lower FSH, larger ovaries and a thicker endometrium compared with the Zuogui Pill group (all P<0.01). However, E+D only significantly increased endometrial thickness (P<0.01) and no significant improvements were observed in the RI of uterine arteries in the three groups. CONCLUSIONS BYHD had a favorable therapeutic effect in patients with DOR by rebalancing hormone levels, promoting ovulation, and repairing the thin endometrium. The combination of tonifying Shen (Kidney), benefiting qi and activating blood circulation may be a promising therapeutic strategy for DOR.
Anti-Mullerian Hormone/pharmacology* ; Drugs, Chinese Herbal ; Female ; Follicle Stimulating Hormone ; Humans ; Luteinizing Hormone ; Ovarian Reserve

OBJECTIVE: Moxibustion, a common therapy in traditional Chinese medicine, has potential benefits for treating decreased ovarian reserve (DOR). The present study investigates the protective effect of moxibustion in a rat model of DOR and explores the possible mechanisms. METHODS: Sixty-four female Sprague-Dawley rats were randomly divided into four groups: control, DOR, moxibustion (MOX), and hormone replacement therapy (HRT). The DOR rat model was established by intragastric administration of 50 mg/kg Tripterygium glycoside suspension (TGS), once daily for 14 days. MOX and HRT treatments were given from the day TGS administration was initiated. The ovarian reserve function was evaluated by monitoring the estrus cycle, morphological changes in ovaries, levels of serum estradiol (E₂), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH), pregnancy rate and embryo numbers. Terminal-deoxynucleotidyl transferase-mediated nick-end-labeling staining was used to identify ovarian granulosa cell apoptosis, while the protein and mRNA expressions of Bax, B-cell lymphoma-2 (Bcl-2), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in ovarian tissues were examined by immunohistochemistry, Western blot and quantitative reverse transcription-polymerase chain reaction. RESULTS: Compared with the DOR group, MOX improved the disordered estrous cycle, promoted follicular growth, reduced the number of atresia follicles, increased the concentrations of serum E₂ and AMH, and decreased serum FSH and LH concentrations. More importantly, the pregnancy rate and embryo numbers in DOR rats were both upregulated in the MOX treatment group, compared to the untreated DOR model. Further, we found that the MOX group had reduced apoptosis of ovarian granulosa cells, increased Bcl-2 expression and reduced expression of Bax. Furthermore, the PI3K/AKT signaling pathway was triggered by the moxibustion treatment. CONCLUSION Moxibustion improved ovarian function and suppressed apoptosis of ovarian granulosa cells in a rat model of DOR induced by TGS, and the mechanism may involve the PI3K/AKT signaling pathway.
Animals ; Female ; Follicle Stimulating Hormone ; Luteinizing Hormone ; Moxibustion ; Ovarian Reserve ; Phosphatidylinositol 3-Kinase/pharmacology* ; Phosphatidylinositol 3-Kinases/metabolism* ; Pregnancy ; Proto-Oncogene Proteins c-akt/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; bcl-2-Associated X Protein/genetics*

OBJECTIVE: To explore the effect of electroacupuncture on endometrial receptivity and the pregnancy outcomes of in vitro fertilization and embryo transfer (IVF-ET) in the patients with diminished ovarian reserve (DOR). METHODS: Sixty-eight patients of DOR undertaken IVF-ET were randomized into an observation group (34 cases, 2 cases dropped off) and a control group (34 cases, 1 case dropped off). In the control group, endometrial preparation was performed according to the routine protocol. In the observation group, on the base of the treatment as the control group, acupuncture was applied to Geshu (BL 17), Shenshu (BL 23), Mingmen (GV 4), Shiqizhui (EX-B 8), Ciliao (BL 32), Zhongliao (BL 33), Tianshu (ST 25), Qihai (CV 6) and Guanyuan (CV 4), etc. Electric stimulation was given at Ciliao (BL 32)-Zhongliao(BL 33), Tianshu (ST 25)-Zigong (EX-CA 1), with disperse-dense wave, 2 Hz/15 Hz in frequency and tolerable current in intensity. Electroacupuncture was given once every two days, 3 times weekly, lasing 3 menstrual cycles till 1 day before embryo transfer. The endometrial thickness and morphology were observed on the day of human chorionic gonadotropin (HCG) of egg retrieval cycle, the day of endometrial transformation in frozen-thawed embryo transfer (FET) cycle and the day of embryo transfer in both groups successively; as well as HCG positive rate, clinical pregnancy rate, embryo implantation rate and live birth rate. RESULTS: In the observation group, the proportion of type A endometrium on the embryo transfer day was higher than those on HCG day of the egg retrieval cycle and the endometrial transformation day of FET cycle (P<0.05), and also higher than that of the control group (P<0.01). In the observation group, HCG positive rate, clinical pregnancy rate, embryo implantation rate and live birth rate were 75.0% (24/32), 71.9% (23/32), 47.4% (27/57) and 56.3% (18/32) respectively, and all higher than 36.4% (12/33), 30.3% (10/33), 18.0% (11/61) and 15.2% (5/33) in the control group separately (P<0.01). CONCLUSION Electroacupuncture improves the endometrial receptivity and IVF-ET pregnancy outcomes in the patients of diminished ovarian reserve.
Chorionic Gonadotropin ; Electroacupuncture ; Endometrium ; Female ; Fertilization in Vitro ; Humans ; Ovarian Diseases ; Ovarian Reserve ; Pregnancy ; Pregnancy Outcome ; Pregnancy Rate

OBJECTIVE: To observe the effect of moxibustion on Nrf2/HO-1 signaling pathway in rats with diminished ovarian reserve (DOR), and to explore the protective mechanism of moxibustion on ovarian reserve function. METHODS: Forty SD rats were randomly divided into a blank group, a model group, a moxibustion group and a hormone group, 10 rats in each group. The rats in the model group, moxibustion group and hormone group were treated with intragastric administration of tripterysium glycosides turbid liquid to prepare DOR model. The rats in the blank group were treated with intragastric administration of sodium chloride solution with the same volume, once a day for 14 days. The rats in the hormone group were treated with hormone sequential therapy for 14 days from the day of modeling; the rats in the moxibustion group were treated with moxibustion at bilateral "Shenshu" (BL 23) or "Guanyuan" (CV 4) and "Zhongwan" (CV 12) from the day of modeling, and the two groups acupoints were alternated every other day, 10 min each time, for 14 consecutive days. The estrus cycle was observed every day by vaginal exfoliated cell smear, and the estrus cycle disorder rate in each group was calculated. After the intervention, the HE staining was used to observe the histological morphology of ovaries; ELISA was used to detect the contents of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E RESULTS: Compared with the blank group, the rate of estrus cycle disorder in the model group was increased ( CONCLUSION Moxibustion could reduce the rate of estrus cycle disorder, improve the level of serum sex hormones and antioxidant stress in DOR rats, and the mechanism may be related to the regulation of Nrf2/HO-1 signaling pathway.
Animals ; Female ; Humans ; Moxibustion ; NF-E2-Related Factor 2/metabolism* ; Ovarian Reserve ; Rats ; Rats, Sprague-Dawley ; Signal Transduction

OBJECTIVE: To explore the correlation between Fragile X mental retardation gene-1 (FMR1) gene CGG repeats with diminished ovarian reserve (DOR). METHODS: For 214 females diagnosed with DOR, DNA was extracted from peripheral blood samples. FMR1 gene CGG repeats were determined by PCR and capillary electrophoresis. RESULTS: Three DOR patients were found to carry FMR1 premutations, and one patient was found to carry gray zone FMR1 repeats. After genetic counseling, one patient and the sister of another patient, both carrying FMR1 permutations, conceived naturally. Prenatal diagnosis showed that both fetuses have carried FMR1 permutations. CONCLUSION FMR1 gene permutation may be associated with DOR. Determination of FMR1 gene CGG repeats in DOR patients can provide a basis for genetic counseling and guidance for reproduction.
Female ; Fragile X Mental Retardation Protein/metabolism* ; Fragile X Syndrome/genetics* ; Humans ; Ovarian Diseases ; Ovarian Reserve/genetics* ; Primary Ovarian Insufficiency/genetics* ; Trinucleotide Repeats/genetics*

BACKGROUND: Mounting evidence implicates an association between ambient air pollution and impaired reproductive potential of human. Our study aimed to assess the association between air pollution and ovarian reserve in young, infertile women. METHODS: Our study included 2276 Korean women who attended a single fertility center in 2016-2018. Women's exposure to air pollution was assessed using concentrations of particulate matter (PM RESULTS: The mean age was 36.6 ± 4.2 years and AMH level was 3.3 ± 3.1 ng/mL in the study population. Average AMH ratio was 0.8 ± 0.7 and low AMH was observed in 10.3% of women (n=235). The average concentration of six air pollutants was not different between the normal ovarian reserve and low AMH groups for all averaging periods. In multivariable models, an interquartile range (IQR)-increase in 1 month-average PM CONCLUSIONS In a cohort of infertile Korean women, there was a suggestive evidence of the negative association between ambient PM concentration and ovarian reserve, highlighting the potential adverse impact of air pollution on women's fertility.
Adult ; Air Pollutants/adverse effects* ; Air Pollution/adverse effects* ; Environmental Exposure/adverse effects* ; Female ; Humans ; Infertility, Female/etiology* ; Ovarian Reserve/physiology* ; Republic of Korea